Bacterial infections remain among the most common and deadly causes of human disease. Infectious diseases are the third leading cause of death in the United States and the leading cause of death worldwide (Binder et al. (1999) Science 284, 1311-1313). Drug-resistant bacteria now cause infections that pose a grave and growing threat to public health. It has been shown that bacterial pathogens can acquire resistance to first-line and even second-line antibiotics (Walsh, C. (2000) Nature 406, 775-781; Schluger, N. (2000) Int. 1. Tuberculosis Lung Disease 4, S71-S75; Raviglione et al., (2001) Ann. NY Acad. Sci. 953, 88-97).
The rifamycin antibacterial agents (e.g., rifampin, rifapentine, rifabutin, rifamixin, and rifalazil) function by inhibiting bacterial RNA polymerase (RNAP), the enzyme responsible for bacterial RNA synthesis (Campbell et al., (2001) Cell 104:901-912; Floss et al. (2005) Chem Rev 105:621-632; Villain-Guillot et al. (2007) Drug Discov Today 12:200-208; Mariani et al. (2009) Curr Med Chem 16:430-454; Ho et al. (2009) Curr Opin Struct Biol 19:715-723). Rifamycins bind to a site on bacterial RNAP adjacent to the RNAP active center and sterically prevent extension of RNA chains. The rifamycins have an exceptionally broad spectrum of antibacterial activity reflecting the conservation of RNAP across Gram-positive and Gram-negative bacterial species. The rifamycins have exceptional antibacterial activity against non-replicating bacteria, slowly replicating, and biofilm-resident bacteria, reflecting the requirement for low levels of RNAP activity for maintenance of the ability to recover from non-replicating and slowly replicating states. The rifamycins are first-line anti-tuberculosis agents, and are the most effective antituberculosis agents in killing non-replicating tuberculosis bacteria. However, the clinical utility of rifamycins is limited by hepatotoxicity that prevents administration of rifamycins at the concentrations that yield highest bacteriocidal kinetics. The clinical utility also is limited by a relatively high frequency of spontaneous resistance (spontaneous resistance frequency of ˜6×10−8). Resistance to rifamycins typically involves substitution of residues in or adjacent to the rifamycin binding site on RNAP—i.e., substitutions that directly decrease binding of rifamycins.
A new drug target within RNAP, the “switch region”, recently was identified, along with compounds, “switch region inhibitors,” that inhibit RNAP through the new drug target (Mukhopadhyay et al. (2008) Cell 135:295-307; Srivastava et al. (2011) Curr Opin Microbiol 14:532-543; WO 05/001034; U.S. Publication 2006-0127905; U.S. Publication 2006-0246479; and WO 07/094799, which are herein incorporated by reference). The switch region is a structural element that mediates opening of the RNAP active-center cleft to bind the DNA template and mediates closing of the RNAP active-center cleft to retain the DNA template. Compounds that bind to the switch region can interfere with opening or closing of the RNAP active-center cleft and can inhibit RNAP allosterically. Since the switch region is conserved across both Gram-positive and Gram-negative bacterial species, inhibitors that function through the switch region typically inhibit RNAP from a broad spectrum of Gram-positive and Gram-negative bacterial species. Since the switch region does not overlap the rifamycin binding site, inhibitors that function through the switch region typically exhibit no cross-resistance with rifamycins.
Four classes of compounds that bind to the switch region, inhibit bacterial RNAP, and exhibit broad-spectrum antibacterial activity have been identified: myxopyronins, corallopyronins, ripostatins, and lipiarmycins (also referred to as tiacumicins and clostomicins). Myxopyronins, corallopyronins, and ripostatins bind to a subregion of the switch region comprising the segment termed “switch 1” and the C-terminal part of the segment termed “switch 2”; this subregion is termed the “SW1/SW2 subtarget.” Lipiarmycins bind to an adjacent, but substantially non-overlapping, subregion of the switch region comprising the N-terminal part of the segment termed “switch 2” and the segment termed “switch 3”; this subregion is termed the “SW2/SW3 subtarget.”
Myxopyronins are currently in preclinical development for use in antibacterial therapy. Novel myxopyronin derivatives that exhibit potent antibacterial activity against a broad-spectrum of Gram-positive and Gram-negative bacteria in vitro, and that exhibit bioavailability upon systemic or oral administration have been synthesized.
Lipiarmycins are currently in clinical use in antibacterial therapy (under the trade names fidaxomicin and Dificid).
Like rifamycins, switch-region inhibitors, including myxopyronins and lipiarmycins, exhibit relatively high frequencies of spontaneous resistance (e.g., spontaneous resistance frequencies of ˜3×10−8 to ˜6×10−8). Resistance to switch-region inhibitors involves substitution of residues in or adjacent to the switch region—i.e., substitutions that directly decrease binding of switch-region inhibitors.
Accordingly, new therapeutic treatments that are useful in the prevention and treatment bacterial infections are needed. Additionally, new approaches to drug development are necessary to combat the ever increasing number of antibiotic-resistant pathogens.